Background
Acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) remain challenging to treat, particularly after relapse following allogeneic hematopoietic cell transplantation (alloHCT). Despite advances in transplantation techniques, disease recurrence occurs in approximately 40-50% of patients, with limited effective salvage options. CD33, a sialic acid-binding immunoglobulin-like lectin expressed on myeloid blasts, has emerged as a promising target for immunotherapy, though previous antibody-based approaches have shown limited efficacy. This unmet need drove the development of VCAR33, a donor-derived CD33-directed chimeric antigen receptor (CAR) T-cell product designed for long-term anti-leukemic surveillance.
Study Design
This phase 1/2 clinical trial evaluated VCAR33 in adults with relapsed or measurable residual disease (MRD)-positive CD33+ AML/MDS after alloHCT. The study employed a dose-escalation design across two arms stratified by disease burden: Arm A included patients with ≥5% bone marrow blasts (n=7), while Arm B included those with <5% blasts or MRD positivity (n=8). Three dose levels were planned: DL1 (1×106 CAR+ T-cells/kg), DL2 (3×106), and DL3 (1×107). The trial terminated early for non-safety reasons before reaching DL3, leaving maximum tolerated dose undetermined. Primary endpoints included safety and feasibility, with secondary endpoints assessing expansion kinetics and antileukemic activity.
Key Findings
Safety Profile
VCAR33 demonstrated manageable toxicity, with cytokine release syndrome (CRS) occurring in 93.3% of patients (all <grade 3). Immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in 26.7% of cases (1 ≥grade 3). One patient (6.7%) developed grade 3 acute graft-versus-host disease within 28 days post-infusion. Notably, no dose-limiting toxicities or treatment-related deaths occurred.
Pharmacodynamics
Transient CAR T-cell expansion occurred in 93.3% of patients, with peak expansion typically observed between days 7-14. Persistence was limited, consistent with allogeneic CAR T-cell products.
Efficacy
The overall response rate was 20% (3/15 patients). In Arm A (high disease burden), two patients achieved complete remission with incomplete count recovery. One Arm B patient attained MRD clearance. The study’s early termination precluded definitive assessment of dose-response relationships.
Expert Commentary
The results suggest VCAR33 may offer a novel approach to preventing relapse post-alloHCT, particularly given the ability to use donor-derived cells without additional manufacturing delays. However, the limited persistence observed raises questions about durability of response. Combining VCAR33 with existing maintenance strategies or exploring repeat dosing could enhance efficacy. The favorable safety profile supports further development, though optimization of cell persistence remains a priority.
Conclusion
This first-in-human study demonstrates that donor-derived anti-CD33 CAR T-cell therapy is feasible with acceptable toxicity in high-risk AML/MDS post-transplant. While responses were modest, the approach warrants further investigation, particularly in MRD-directed settings or in combination with other therapeutics. Future studies should explore strategies to enhance persistence and evaluate optimal timing relative to transplant.
Funding and Registration
This trial was funded by the National Cancer Institute and industry partners. Registered at ClinicalTrials.gov (#NCT05984199).